Recent Advances in Primary Biliary Cirrhosis

80 Pages·2014·4.06 MB·English

by  Alicia Zambri

Recent Advances in Primary Biliary Cirrhosis

Disease Pathways and Potential Targets of Therapy

Ulrich H.W. Beuers, MD
Department of Gastroenterology & Hepatology
Tytgat Institute for Liver and Intestinal Research
Academic Medical Centre
University of Amsterdam
The Netherlands
Primary Biliary Cirrhosis

Characteristics

Sex (f:m) 9 : 1
Age 40 - 60 Sherlock and Summerfield, 1991
Symptoms:
Survival without treatm. 7.5-16 years
•  Fatigue
Cholestatic enzyme
•  Itch
pattern AP, γGT •  “Dry eye, dry mouth“
Autoantibodies AMA (anti-PDC-E2) •  …
Courtesy of Ulrich H. W. Beuers, MD.
Primary Biliary Cirrhosis
Pathogenesis
Cholestasis Liver cell
Aggravation
Immune- with damage,
of bile duct
Liver
mediated retention of apoptosis,
injury by
bile duct hydrophobic necrosis, failure
hydrophobic
injury bile acids in fibrosis,
bile acids
liver cirrhosis
Beuers U, et al. Hepatology. 1998;28:1449-1453.
Primary Biliary Cirrhosis
- Pathogenesis -
•  Genetic predisposition
•  Exogenous factors
•  Endogenous factors
Primary Biliary Cirrhosis
- Pathogenesis -
•  Genetic predisposition

Monozygotic twins: >60% PBC
Selmi C, et al. Gastroenterology. 2004;127:485-492.
Family members: 6% PBC

GWAS*: HLA-DQ-B1, Il12A, Il12B2, STAT4,…
Hirschfield GM, et al. N Engl J Med. 2009;360:2544-2555.
•  Exogenous factors

•  Endogenous factors
*GWAS: Genome-wide association study.
Primary Biliary Cirrhosis
- Pathogenesis -
•  Genetic predisposition
•  Exogenous factors
•  Endogenous factors
Sequence Homology of the Human Pyruvate Dehydrogenase
Complex (PDC-E2 ) with Bacterial Proteins
208-237
Inner lipoyl domain of the E2 subunit of the pyruvate dehydrogenase complex (PDC-E2)
(Left graphic) With permission from Migliaccio C, et al. Hepatology. 2001;33:792-801.
(Right graphic) With permission from Selmi C, et al. Hepatology. 2003;38:1250-1257.
Model of AMA Formation and Cholangiocyte Damage in
Primary Biliary Cirrhosis
IgA AMA
transfer via
cholangiocytes
With permission from Rieger R, Gershwin ME. J Autoimmun. 2007;28:76-84.
Primary Biliary Cirrhosis
- Pathogenesis -
•  Genetic predisposition
•  Exogenous factors
•  Endogenous factors
Primary Biliary Cirrhosis

Characteristics
Too low
HCO - ?
3

Prieto J, et al. Gastroenterology. 1993;105:572-578.
Medina JF, et al. Hepatology. 1997;25:12-17.
Prieto J, et al. Gastroenterology. 1999;117:167-172.
Sex (f:m) 9 : 1
Banales JM, et al. Hepatology. 2012;56:687-697.
Age 40 - 60 Sherlock and Summerfield, 1991
Signs & symptoms:
Survival without treatm. 7.5-16 years
•  Fatigue
Cholestatic enzyme
•  Itch
Pattern AP, γGT •  “Dry eye, dry mouth“
Autoantibodies AMA (anti-PDC-E2) •  …
Courtesy of Ulrich H.W. Beuers, MD.